1. Field of the Invention
This invention relates to the use of certain derivatives of 5-hydroxy and 5-methoxy 2-aminopyrimidines and the pharmaceutically-acceptable salts thereof to inhibit interleukin-1 production in a mammal. This invention also relates to the use of such compounds for treating interleukin-1 mediated disorders and dysfunctions such as bone and connective tissue metabolism disorders and immune dysfunction in a mammal. The methods of this invention comprise administering an effective amount of the compounds and salts of this invention to such a mammal.
2. General Background
Certain 5-hydroxy and 5-alkoxy pyrimidines of the formula ##STR2## and the pharmaceutically-acceptable salts thereof wherein, inter alia, R.sub.1 is H; R.sub.2 is H, (C.sub.1 -C.sub.15)alkyl or (C.sub.7 -C.sub.20)phenylalkyl which may be substituted in the phenyl by one or two of fluoro or chloro; R.sub.3 is (C.sub.1 -C.sub.6)alkyl; R.sub.4 is H or (C.sub.1 -C.sub.6)alkyl; and R.sub.5 is H or (C.sub.1 -C.sub.6)alkyl are disclosed and claimed in U.S. Pat. No. 4,711,888 which is assigned to the assignee hereof. That patent discloses that those compounds are inhibitors of leukotriene synthesis and are useful for the treatment of pulmonary, inflammatory, allergic and cardiovascular diseases as well as being cytoprotective and, therefore, useful in the treatment of peptic ulcers. Specific utilities disclosed for those compounds include treatment of asthma, bronchitis, pulmonary diseases, such as pulmonary hypertension and hypoxia, peptic ulcers, psoriasis, arthritis, inflammatory bowel disease or cardiovascular spasm, such as acute myocardial infarctions. The teachings thereof are incorporated herein by reference.
Certain 2-amino-5-hydroxy-4-methyl pyrimidine derivatives of the formula ##STR3## and the pharmaceutically-acceptable acid addition salts thereof wherein, inter alia, R is H or (C.sub.1 -C.sub.15)alkyl and R' is (C.sub.1 -C.sub.15)alkyl are disclosed and claimed in U.S. Pat. No. 4,554,276 which is assigned to the assignee hereof. That patent discloses that those compounds are inhibitors of leukotriene synthesis and are useful in the treatment of pulmonary, inflammatory and cardiovascular diseases, cancer and psoriasis. Further, those compounds are disclosed as having cytoprotective activity and therefore are also useful in the treatment of peptic ulcers. A method of treating gastrointestinal disorders with compounds disclosed in U.S. Pat. No. 4,554,276 discussed above is disclosed and claimed in U.S. Pat. No. 4,673,677. Both U.S. Pat. No. 4,554,276 and U.S. Pat. No. 4,673,677 are assigned to the assignee hereof and the teachings thereof are incorporated herein by reference.
Interleukin-1 (IL-1) has been reported to stimulate bone resorption both in vitro and in vivo. Hayward, M. and Fiedler-Nagy, Ch., Agents and Actions, 22, 251-254 (1987). It is also reported therein that IL-1, inter alia, induces the production of prostaglandin E.sub.2 (PGE.sub.2) PGE.sub.2 is a stimulator of bone resorption and has been implicated in bone loss. Hayward, M. A. and Caggiano, T. J., Annual Reports in Medicinal Chemistry, 22, Sect. IV, Chapter 17, 172-177 (1987). Osteoporosis is defined as a debilitory loss of bone mineral which results in higher fracture rates. See Hayward, M. A. and Caggiano, T. J., supra and references cited therein.
Interleukin-1 has been reported to be involved in the pathogenesis of many diseases. See Dinarello, C. A., J. Clin. Immunol., 5, 287-297 (1985), the teachings of which are incorporated herein by reference. Further still, elevated levels of IL-1 like material have been found to be associated with psoriasis. Camp, R. D., et al., J. Immunol., 137, 3469-3474 (1986).
The non-steroidal anti-inflammatory agent etodolac, 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b] indole-1-acetic acid, has been disclosed in U.S. Pat. No. 4,677,132 to lower PGE.sub.2 and reduce bone resorption. Etodolac has the formula ##STR4##
It has been reported that therapeutic levels of nonsteroidal anti-inflammatory agents such as indomethacin and ibuprofen do not reduce IL-1 production. Similarly, cyclosporine A had no such effect. Corticosteroids, however, are effective in reducing IL-1 production. Dinarello, C. A., supra. Certain lipoxygenase inhibitors such as 5,8,11,14-eicosatetraynoic acid (ETYA) and 3-amino-1,3-trifluoromethylphenyl-2-pyrazoline (BW755C) have been reported to decrease in vitro production of leukocytic pyrogen (putative IL-1) from human monocytes. Dinarello, C. A., et al., Int. J. Immunopharmac., 6, 43-50 (1984).
However, until the invention herein, there was no report of use or intent to use the compounds or salts of this invention to inhibit IL-1 production and to treat IL-1 mediated disorders and dysfunctions such as certain bone and connective tissue metabolism disorders and certain immune dysfunctions with such compounds nor any appreciation of their role in such treatments.